Use of non-metallic cest agents for mri monitoring of nanoparticle delivery

Abstract

The present invention includes drug-loaded, polymer nanoparticles and liposomes further incorporating a non-paramagnetic, bioorganic CEST agent. The CEST agent allows for an alternative approach to accomplish MR-compatible in vivo tracking of drug-loaded polymer nanoparticles and liposomes, including simultaneous multi-color mapping of more than one particle type, or of the same particle type delivered via two different routes (e.g., systemic versus local). Additionally, the present invention can include a library of biodegradable diamagnetic (DIA)CEST agents. These DIACEST agents can be incorporated into nanoparticle-based delivery systems, such as stealth liposomes loaded with doxorubicin and stealth polymer nanoparticles loaded with paclitaxel. These systems can be tracked, according to an embodiment of the present invention using CEST-based MRI (compared to SPECT/CT) as a method to monitor the efficiency with which the nanoparticles reach the targeted tumors and how long they persist. Measured particle persistence times are also used to guide the spacing between doses.

1 . An agent for use in conjunction with magnetic resonance (MR) imaging comprising:
 a biocompatible chemical exchange saturation transfer (CEST) agent, said biocompatible CEST agent being configured to create contrast in an MR image, wherein the contrast is detectable using a saturation transfer CEST method of MR imaging;   a drug delivery system;   a therapeutic agent; and   wherein the biodegradable CEST agent, the drug delivery system, and therapeutic agent are combined to form a particle.   
     
     
         2 . The agent of  claim 1  wherein the particle further comprises a nanoparticle. 
     
     
         3 . The agent of  claim 1  wherein the CEST agent comprises a non-metallic DIACEST agent. 
     
     
         4 . The agent of  claim 1  wherein the agent is configured for use as systemic nanoparticle-based chemotherapy. 
     
     
         5 . The agent of  claim 1  wherein the agent is configured for use as local nanoparticle-based chemotherapy. 
     
     
         6 . The agent of  claim 1  wherein the CEST agent further comprises at least one of a polypeptide or organic heterocycle. 
     
     
         7 . The agent of  claim 1  wherein the CEST agent further comprises at least one of a peptide that is ring NH-rich, backbone NH-rich, guanidyl NH 2 -rich, or OH-rich. 
     
     
         8 . The agent of  claim 1  wherein the CEST agent further comprises a macromolecule with multiple amide or imino groups. 
     
     
         9 . The agent of  claim 1  wherein the drug delivery system comprises a mucus penetrating particle. 
     
     
         10 . The agent of  claim 1  wherein the drug delivery system comprises one of a stealth liposome or a stealth poly(lactic-co-glycolic acid)-co-polyethylene glycol (PLGA-PEG) particle. 
     
     
         11 . The agent of  claim 1  wherein the therapeutic agent takes the form of one of doxorubicin or paclitaxel. 
     
     
         12 . A method for tracking a delivery of a therapeutic agent in a subject comprising:
 providing a particle containing a biocompatible CEST contrast agent, a therapeutic agent, and a drug delivery system, wherein the biocompatible CEST agent is configured to create contrast in an MR image detectable using a saturation transfer CEST method of MR imaging;   delivering the particle to the subject;   using the saturation transfer CEST method of MR imaging to obtain an MR image of the subject; and   using the MR image of the subject to track the delivery of the therapeutic agent using the contrast created by the CEST agent.   
     
     
         13 . The method of  claim 12  further comprising using the particle to treat cancer. 
     
     
         14 . The method of  claim 13  further comprising using the particle to treat cervical cancer. 
     
     
         15 . The method of  claim 12  further comprising delivering the particle to the subject systemically. 
     
     
         16 . The method of  claim 12  further comprising delivering the particle to the subject locally. 
     
     
         17 . The method of  claim 12  further comprising building a library of available CEST contrast agents for use in conjunction with the method. 
     
     
         18 . The method of  claim 12  further comprising using multicolor MR imaging. 
     
     
         19 . The method of  claim 12  further comprising using information from the image of the subject to determine dose frequency for the therapeutic agent. 
     
     
         20 . The method of  claim 12  further comprising using information from the image of the subject to determine clearance of the therapeutic agent.